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Review 1: "Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue"

Published onDec 29, 2022
Review 1: "Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue"
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key-enterThis Pub is a Review of
Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue

AbstractPost-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker.A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables ‘Bell score’, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis.An age effect on VD was observed between patients and controls (p<0.0001). Gender analysis yielded that women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). The PCS patients showed significantly lower VD of ICP as compared to the controls (p=0.0001, [CI: 0.32; 1]). Moreover, considering PCS patients, the mixed model reveals a significant difference between chronic fatigue (CF) and without CF in VD of SVP (p=0.0033, [CI: -4.5; -0.92]). The model included age, gender and the variable ‘Bell score’, representing a subjective marker for CF. Consequently, the retinal microcirculation might be an objective biomarker in subjective-reported chronic fatigue of patients with PCS.

RR:C19 Evidence Scale rating by reviewer:

Not informative. The flaws in the data and methods in this study are sufficiently serious that they do not substantially justify the claims made. It is not possible to say whether the results and conclusions would match that of the hypothetical ideal study. The study should not be considered as evidence by decision-makers.



The authors investigate an interesting idea: the use of retinal microcirculation measurements as biomarkers for post-covid syndrome. They correctly state that: “the eye as window in the human body might offer a diagnostic option by measuring retinal microcirculation objectively”. In fact, published literature describes several ophthalmic manifestations after covid infection or vaccination. However, claims are not substantially supported by the data and methods used; and decision-makers should consider the claims in this study not actionable based on the methods and data.

Major study limitations are the following:

The authors have not presented and analyzed possible study confounders that may be affecting retinal microcirculation. This is a significant limitation of the study as any association identified is likely to be due to the presence of possible confounders that no adjustment has been made for. Some of these might be the presence of diabetes mellitus, hypertension or other cardiovascular conditions, previous covid vaccination, ophthalmic or systemic medications. The fact that no apparent “retinal affection” was observed in study eyes does not exclude that retinal microcirculation might have been affected by possible confounders.

The case/control ratio is not being implemented as recommended. The authors are including 173 cases and 28 controls (6.17 to 1 ratio). The recommended case/control ratio is between 1 to 2 and 1 to 4.

The inclusion/exclusion criteria used are not presented. Were there any patients excluded for any specific reason and how have been patients included selected?

The authors do not clarify what the covid status of the controls is. Have any of them been also previously affected by covid or not? If yes, was it a symptomatic or an asymptomatic course and what was the time interval between infection and study inclusion? Was any antibody test performed to controls too?

There is an opposite trend for vessel density in the intermediate capillary plexus in patients with post-covid syndrome and in the superficial vascular plexus in patients with chronic fatigue. The authors should have elaborated on that.

The authors are not following the general recommendations about what to include in each part of the paper. For example, study results are repeated in the discussion section (first paragraph of the discussion section). Similarly, description of OCTA analysis method (third paragraph of the discussion section) is part of the study methods and not the study discussion. The authors should stick to the general guidelines about what to include in each part of a scientific paper.

No sample size calculation method is presented. Was there any hypothesis or previous data to support the sample size used in the study?

The authors are not adequately discussing previous research about ocular findings after covid infection. There is a significant amount of relevant papers and the authors should discuss more extensively how their hypothesis and their data come to complement existing literature. Vascular and inflammatory ophthalmic manifestations have been previously described both after covid infection and vaccination and they should be presented and discussed by the authors.

The authors are encouraged to continue working on their hypothesis based on firm research methodology but major issues have been identified in the current study.


Since our solicitation of reviews, this preprint has been published in the International Journal of Molecular Sciences and the link to the published manuscript can be found here.

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